Semi-synthetic conversion of paclitaxel to docetaxel

ABSTRACT

A process is provided for the semi-synthesis of taxane derivatives useful in the preparation of docetaxel, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction of protecting the C-2′, C-7 and C-10 and introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position in paclitaxel and subsequently conversion to docetaxel, and derivatives used therein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a semi-synthesis of taxane derivativesuseful in the preparation of docetaxel, from pure or crude paclitaxel orrelated taxane starting material, in particular, the semi-synthesis ofprotected taxane derivatives in a one pot reaction and its conversion todocetaxel.

2. Description of the Related Art

The taxane family of terpenes has received much attention in thescientific and medical community because the members of this family havedemonstrated broad spectrum anti-leukemic and tumor-inhibitory activity.Docetaxel (1, Taxotere), a semi-synthetic analog, and paclitaxel (2,Taxol), a complex diterpene isolated from the bark of the Pacific yewtree (Taxus brevifolia) are arguably the most outstanding cancerchemotherapeutic substances discovered in recent times. For example,paclitaxel has been found to have activity against different forms ofleukemia and against solid tumors in the breast, ovary, brain, and lungin humans. While paclitaxel can be obtained from the yew tree orsemi-synthetically, only the latter option is currently available forthe formation of non-natural docetaxel. The partial synthesis of thisimportant compound has generally been accomplished throughesterification of a derivative of the (2R, 3S) phenylisoserine sidechain with a protected form of 10-deacetylbaccatin III, a comparativelyabundant natural product also present in the yew tree.

As disclosed in U.S. Pat. No. 4,814,470, taxotere has been found to havevery good anti-tumor activity and better bio-availability thanpaclitaxel. Taxotere is similar in structure to paclitaxel, havingt-butoxycarbonyl instead of benzoyl on the amino group at the 3′position, and a hydroxy group instead of the acetoxy group at the C-10position.

Docetaxel and paclitaxel may be prepared semi-synthetically from10-deacetylbaccatin III or baccatin III as set forth in U.S. Pat. Nos.4,924,011 and 4,924,012, by the reaction of a β-lactam and a suitablyprotected 10-deacetylbaccatin III or baccatin III derivative as setforth in U.S. Pat. No. 5,175,315, by a method using an oxazolinecompound as set forth in International Patent Kokai No. Hei 7-504444, bya method using thioester compound as set forth in International PatentKokai No. Hei 10-505360 or by a method using cinnamic acid as set forthin Tetrahedron, Vol. 42, p. 4451, 1986, etc. 10-deacetylbaccatin III(10-DAB, 3) and Baccatin III (4) can be separated from mixturesextracted from natural sources such as the needles, stems, bark orheartwood of numerous Taxus species and have the following structures.

Although much of the research towards the semi-synthesis of paclitaxeland taxotere has involved 10-deacetylbaccatin III as the startingmaterial, other taxanes from the Taxus species, such as9-dihydro-13-acetylbaccatin III (9-DHB, 5), present in the Canadian yew(Taxus Canadensis), cephalomannine (6), 10-deacetyl taxol (10-DAT, 7),7-xylosyl taxol (8), 10-deacetyl-7-xylosyl taxol (9) and a number of7-epi-taxanes have been collected and identified.

As disclosed in U.S. patent application Ser. No. 10/695,416, whichapplication is assigned to the assignee of the present invention,docetaxel and paclitaxel may also be prepared semi-synthetically from9-dihydro-13-acetylbaccatin III.

However, the above methods thus far developed involve subjects such asreaction under the conditions of extremely low temperatures, generationof diastereomers, use of asymmetry controlling agents, and the reactionunder strongly alkaline conditions, which cause problems upon theindustrialization thereof.

Accordingly, there remains a need for new and improved processes for thepreparation of taxane derivatives and their conversion to docetaxel, andalso for the preparation of such taxane intermediates from crude andpartially purified mixtures comprising a plurality of taxanes. Thepresent invention addresses these needs and provides further relatedadvantages.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a simple process for conversion ofpaclitaxel or a paclitaxel-containing material to its syntheticanalog—docetaxel. Accordingly, one embodiment of the present inventionprovides a process for producing a taxane intermediate under mildconditions using a pure or partially purified paclitaxel or a paclitaxelanalog as a starting material, the taxane intermediate can later be usedas a precursor to docetaxel. The process comprises protecting a compoundof Formula (I):

wherein, R¹ is alkyl, alkenyl or aryl; and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy. In particular,the process comprises: protecting one or more hydroxy groups at theC-2′, C-7 and C-10 positions of the taxane; and introducing a t-Bocgroup at the nitrogen of the amide group at the C-3′ position of thetaxane to provide a C-2′, C-7, C-10 and N-t-Boc protected paclitaxelderivative, wherein the steps of protecting one or more hydroxy groupsand introducing the t-Boc group comprises combining, in a one potreaction, the taxane with a hydroxy protecting group and a t-Boc agent.

In another embodiment, the hydroxy protecting groups at the C-2′, C-7and C-10 positions can be the same or different.

In another embodiment, the step of protecting one or more hydroxy groupsat the C-2′, C-7 and C-10 positions of the taxane is carried out in thepresence of a base.

In yet another embodiment, the step of protecting one or more hydroxygroups at the C-2′, C-7 and C-10 positions of the taxane is carried outin the presence of an acid.

A further embodiment of the present invention provides a process forpreparing docetaxel from a taxane of Formula (I):

wherein, R¹ is alkyl, alkenyl or aryl; and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy, the processcomprising: protecting one or more hydroxy groups at the C-2′, C-7 andC-10 positions of the taxane; introducing a t-Boc group at the nitrogenof the amide group at the C-3′ position of the taxane to provide aprotected paclitaxel derivative having an urea linkage at the C-3′position; selectively removing the —C(O)R¹ group from the urea linkageto provide a protected docetaxel; and converting the protected docetaxelto docetaxel by removing the hydroxy-protecting groups at the C-2′, C-7and C-10 positions, wherein the step of protecting one or more hydroxygroups at C-2′, C-7 and C-10 positions, and introducing the t-Boc groupat the nitrogen site of the amide group of the taxane comprisescombining, in a one pot reaction, the taxane of Formula (I) with ahydroxy protecting agent and a t-Boc agent, and wherein the step ofselectively removing the —C(O)R¹ group comprises subjecting theprotected paclitaxel derivative having the urea linkage to a first base.

In another embodiment, the hydroxy protecting groups at the C-2′, C-7and C-10 positions can be the same or different.

In another embodiment, the step of protecting one or more hydroxy groupsat the C-2′, C-7 and C-10 positions of the taxane is carried out in thepresence of a second base.

In yet another embodiment, the step of protecting one or more hydroxygroups at the C-2′, C-7 and C-10 positions of the taxane is carried outin the presence of an acid.

In addition, the present invention provides a simplified and efficientprocess for preparing docetaxel from an initial mixture of taxanes,wherein the initial mixture comprises paclitaxel and at least oneadditional taxane selected from the group of 10-deacetylbaccatin III,9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine,10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol, theprocess comprising the steps of: protecting the hydroxy groups at theC-2′ and C-7 positions of paclitaxel; introducing a t-Boc group at thenitrogen of the amide group at the C-3′ position of paclitaxel toprovide a protected paclitaxel derivative having an urea linkage at theC-3′ position; selectively removing the benzoyl group from the urealinkage to provide a protected docetaxel; and converting the protecteddocetaxel to docetaxel by removing the hydroxy-protecting groups at theC-7, C-2′ and C-10 positions, wherein the step of protecting the hydroxygroups at C-2′ and C-7 positions, and introducing a t-Boc group at thenitrogen site of the amide group of paclitaxel are carried out in a onepot reaction wherein the mixture containing paclitaxel is combined witha hydroxy protecting agent and a t-Boc agent; and wherein the step ofselectively removing the benzoyl group comprises subjecting theprotected paclitaxel derivative having the urea linkage to a first base.

In another embodiment, the step of protecting the hydroxy group at theC-2′ and C-7 position of paclitaxel further comprises protecting one ormore hydroxy groups at the C-2′, C-7 and C-10 positions of each taxanein the initial mixture having a hydroxy group at these positions.

Another embodiment of the present invention provides a process ofconverting a taxane of Formula (I)

wherein, R¹ is alkyl, alkenyl or aryl, and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy, to docetaxel,via a primary amine intermediate. The process comprises: introducing anitroso group (—NO) at the nitrogen of the amide group at the C-3′position of the taxane to provide a N-nitrosoamide intermediate;hydrolyzing the N-nitrosoamide intermediate to provide a N-nitrosoamineintermediate; reducing the N-nitrosoamine intermediate to provide aprimary amine intermediate; and converting the primary amine derivativeto docetaxel,

These and other aspects of the invention will be apparent using chemicalreactions that are mild, efficient and selective as described herein,upon reference to the attached figures and following detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a chemical route for the preparation of a protectedtaxane derivative from paclitaxel or paclitaxel containing material, andthe conversion of such derivative to docetaxel according to the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention relates to processes forconverting paclitaxel, paclitaxel containing material or otherpaclitaxel derivatives to docetaxel.

I. Definitions

As used herein, the following terms have the following meanings.

“Silica matrix” is a solid media containing a silicate which is used asan adsorbent or column material in chromatographic separations,including (but not limited to) ordinary silica, Florisil, porous silicagels or any physical formulation of a silicate for use inchromatographic procedures.

“Taxane-containing material” refers to selected parts of a plant, planttissues, cell cultures, microorganisms or extracts with extractabletaxanes, including paclitaxel, 10-deacetylbaccatin III (10-DAB),baccatin III (BACC III), 9-dihydro-13-acetylbaccatin III (9-DHB),cephalomannine, 10-deacetyl taxol (10-DAT), 7-xylosyl taxol and10-deacetyl-7-xylosyl taxol.

“Crude taxane extract” refers to a composition obtained from ataxane-containing material by treating the taxane-containing materialwith at least one solvent.

“Partially purified taxane extract” refers to a paclitaxel enrichedcomposition obtained from the chromatographic separation and/orrecrystallization of a crude or partially purified taxane extract.

“Waste stream fractions” refers to fractions collected following thechromatographic separation and collection of paclitaxel enrichedfractions from a crude or partially purified taxane extract by, forexample, the process of U.S. Pat. No. 6,136,989.

“Waste mother liquors” refers to mother liquors collected following therecrystallization of a crude or partially purified taxane extract by,for example, the process of U.S. Pat. No. 6,136,989.

“Hydroxy-protecting group” refers to any derivative of a hydroxy groupknown in the art which can be used to mask the hydroxy group during achemical transformation and later removed under conditions resulting inthe hydroxy group being recovered without other undesired effects on theremainder of the molecule. Many esters, acetals, ketals and silyl ethersare suitable protecting groups. Examples of hydroxy-protecting groupsinclude, without limitation, formyl, acetyl (Ac), benzyl (PhCH₂),1-ethoxyethyl (EE), methoxymethyl (MOM), (methoxyethoxy)methyl (MEM),(p-methoxyphenyl)methoxymethyl (MPM), tert-butyldimethylsilyl (TBS),tert-butyidiphenylsilyl (TBPS), tert-butoxycarbonyl (tBoc, t-Boc, tBOC,t-BOC), tetrahydropyranyl (THP), triphenylmethyl (Trityl, Tr),2-methoxy-2-methylpropyl, benzyloxycarbonyl (Cbz), dichloroacetyl,trichloroacetyl (OCCCl₃), 2,2,2-trichloroethoxycarbonyl (Troc),benzyloxymethyl (BOM), tert-butyl (t-Bu), triethylsilyl (TES),trimethylsilyl (TMS), triisopropylsilyl (TIPS), propionyl, isopropionyl,pivalyl, dimethylisopropylsilyl, diethylisopropylsilyl,methyldiphenylsilyl, dimethylphenylsilyl, tert-butyldiphenylsilyl,tribenzylsilyl, triphenylsilyl, trichloroethoxycarbonyl, benzyl,para-nitrobenzyl, para-methoxybenzyl, benzoyl, methoxyethyl,para-methoxyphenyl, tetrahydrofuranyl, alkylsulfonyl and arylsulfonyl.The related term “protected hydroxy group” or “protected —OH” refers toa hydroxy group that is bonded to a hydroxy-protecting group. Generalexamples of protected hydroxy groups include, without limitation,—O-alkyl, —O-acyl, acetal, and —O-ethoxyethyl (OEE), where some specificprotected hydroxy groups include, formyloxy, acetoxy, propionyloxy,chloroacetoxy, bromoacetoxy, dichloroacetoxy, trichloroacetoxy,trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy,benzoylformoxy, p-nitro benzoyloxy, ethoxycarbonyloxy,methoxycarbonyloxy, propoxycarbonyloxy,2,2,2-trichloroethoxycarbonyloxy, benzyloxycarbonyloxy,tert-butoxycarbonyloxy, 1-cyclopropylethoxycarbonyloxy, phthaloyloxy,butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyoxy,succinyloxy and pivaloyloxy, phenylacetoxy, phenylpropionyloxy,mesyloxy, chlorobenzoyloxy, para-nitrobenzoyloxy, para-tert-butylbenzoyloxy, capryloyloxy, acryloyloxy, methylcarbamoyloxy,phenylcarbamoyloxy, naphthylcarbamoyloxy, and the like. The related term“hydroxy protecting agent” refers to a reagent that introduces a hydroxyprotecting group to a free hydroxy functionality. Typically, a hydroxyprotecting agent comprises a hydroxy protecting group as those listedabove and a leaving group, such as a halide or a triflate. When thehydroxy protecting group is an alkyl, the hydroxy protecting agent isreferred herein as an alkylating agent. The alkyl moiety of thealkylating agent can be optionally substituted by aryl, alkoxy, oraryloxy. Suitable alkylating agent includes benzyl bromide, benzylchloride, methoxymethyl chloride, ethyl vinyl ether, and benzyloxymethylchloride. Similarly, when the hydroxy protecting group is an acyl orsilyl, the hydroxy protecting agent can be referred herein as anacylating agent or silylating agent, respectively. Suitable acylatingagent includes, but not limited to, Boc₂O and acetoxyacetyl chloride.Suitable silylating agents includes TMSCI (trimethylsilyl chloride),TESCI (triethylsilyl chloride), etc. More exemplary hydroxy-protectinggroups and hydroxy protecting agents are described in, e.g., C. B. Reeseand E. Haslam, “Protective Groups in Organic Chemistry,” J. G. W.McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4,respectively, and T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” Second Edition, John Wiley and Sons, New York, N.Y.,1991, Chapters 2 and 3.

“Thiol-protecting group” refers to any derivative of a thiol group knownin the art which can be used to mask the thiol group during a chemicaltransformation and later removed under conditions resulting in the thiolgroup being recovered without other undesired effects on the remainderof the molecule. Examples of thiol-protecting groups include, withoutlimitation, triphenylmethyl (trityl, Trt), acetamidomethyl (Acm),benzamidomethyl, 1-ethoxyethyl, benzoyl, and the like. The related term“protected thiol group” refers to a thiol group that is bonded to athiol-protecting group. General examples of protected thiol groupsinclude, without limitation, —S-alkyl (alkylthio, e.g.,C₁-C₁₀alkylthio), —S-acyl (acylthio), thioacetal, —S-aralkyl(aralkylthio, e.g., aryl(C₁-C₄)alkylthio), where some specific protectedthiols groups include methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio,isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio,cyclobutylthio, cyclopentylthio and cyclohexylthio, benzylthio,phenethylthio, propionylthio, n-butyrylthio and iso-butyrylthio.Thiol-protecting groups and protected thiol groups are described in,e.g., C. B. Reese and E. Haslam, “Protective Groups in OrganicChemistry,” J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973,Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” Second Edition, John Wiley andSons, New York, N.Y., 1991, Chapters 2 and 3.

The following Table shows the chemical structures of some protectinggroups, as well as the nomenclatures used to identify these chemicalstructures. TABLE 1 Acetyl (Ac)

Acetoxy (—OAc)

Dichloro- acetyl

Dichloro- acetoxy

Triethyl- silyl (TES)

Triethyl- siloxy (—OTES)

Benzoyl

Benzoyloxy

t-Butyloxycarbonyl (tBOC)

t-Butoxycarbonyloxy (—O—tBOC)

para-Methoxyphenyl (PMP)

“Alkyl” refers to an optionally substituted hydrocarbon structure,containing no saturation, wherein the carbons are arranged in a linear,branched or cyclic manner, including combinations thereof. Lower alkylrefers to alkyl groups of 1 to 5 carbon atoms. Examples of lower alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyland the like. “Cycloalkyl” is a subset of alkyl and includes mono orbi-cyclic hydrocarbon groups of from 3 to 13 carbon atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,norbornyl, adamantyl and the like. When an alkyl residue having aspecific number of carbons is named, all geometric isomers having thatnumber of carbons are intended to be encompassed; thus, for example,“butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl;propyl includes n-propyl and isopropyl.

“Alkenyl” refers to an optionally substituted alkyl group having atleast one site of unsaturation, i.e., at least one double bond.

“Alkynyl” refers to an optionally substituted alkyl group having atleast one triple bond between two adjacent carbon atoms.

“Alkoxy” refers to a radical of the formula —O-alkyl. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to five carbons.

“Alkoxycarbonyl” refers to a radical of the formula —C(O)-alkoxy,wherein alkoxy is as defined herein.

“Aryl” refers to optionally substituted phenyl or naphthyl. Exemplarysubstituents for aryl include one or more of halogen, hydroxy, alkoxy,aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto,alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonylwhere the alkoxy portion contains 1 to 15 carbons, aryloxycarbonyl wherethe aryloxy portion contains 6 to 20 carbon, or heteroarylcarbonyl wherethe heteroaryl portion contains 3 to 15 carbon atoms.

“Aryloxy” refers to a radical of the formula —O-aryl, wherein aryl isdefined as above. Representative aryloxy includes phenoxy.

“Aryloxycarbonyl” refers to a radical of the formula —C(O)-aryloxy,wherein aryloxy is as defined herein.

“Heteroaryl” refers to an optionally substituted 5- or 6-memberedheteroaromatic ring containing 1-3 heteroatoms selected from O, N or S;a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-3heteroatoms selected from O, N or S; or a tricyclic 13- or 14-memberedheteroaromatic ring system containing 1-3 heteroatoms selected from O, Nor S. Exemplary aromatic heterocyclic rings include, e.g., imidazole,pyridine, indole, thiophene, benzopyranone, thiazole, furan,benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

“Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10-memberedbicyclic, heterocyclic ring which is either saturated, unsaturated oraromatic, and which contains from 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen and sulfur, and wherein the nitrogen andsulfur heteroatoms may be optionally oxidized, and the nitrogenheteroatom may be optionally quaternized, including bicyclic rings inwhich any of the above heterocycles are fused to a benzene ring. Theheterocycle may be optionally substituted with 1-5 substituents. Theheterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined above. Thus, in addition tothe heteroaryls listed above, heterocycles also include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Acyl” refers to a radical of the formula —C(═O)—R, wherein R is alkyl,alkenyl, alkynyl, aryl, alkoxy, aryloxy, heterocycle or heteroaryl,where alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, heterocycle andheteroaryl are as defined herein. Representative acyl groups includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, and the like.Lower-acyl refers to groups containing one to five carbons.

“Leaving group” refers to a chemical moiety that may be displaced duringa substitution or elimination reaction. Exemplary leaving groups includehalogen (e.g., bromide and chloride), triflate and tosyl.

“Halogen” refers to fluoro, chloro, bromo or iodo.

“Oxo” refers to ═O.

“Hydrocarbonyl” refers to alkyl, alkenyl, alkynyl or aryl.

“Metal alkoxide” refers to a base of a general formula MO-alkyl, whereinM is a Group I, II, III or transition metal. Representative metalalkoxides are lithium t-butoxide, sodium t-butoxide, potassiumt-butoxide, calcium methoxide, lithium methoxide.

“Metal hydroxide” refers to a base of a general formula M-OH, wherein Mis a Group I, II, III or transition metal. Representative metalhydroxide are lithium hydroxide (LiOH), sodium hydroxide (NaOH), calciumhydroxide (Ca(OH)₂).

The term “substituted” as used herein means any of the above groups(e.g., alkyl, alkoxy, acyl, aryl, heteroaryl and heterocycle) wherein atleast one hydrogen atom is replaced with a substituent. In the case ofan oxo substituent (“═O”) two hydrogen atoms are replaced. Substituentsinclude halogen, hydroxy, oxo, alkyl, aryl, alkoxy, aryloxy, acyl,mercapto, cyano, alkylthio, arylthio, heteroarylthio, heteroaryl,heterocycle, —NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(c)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b), —NR_(a)SO₂R_(b), —C(═O)NR_(a)R_(b), —OC(═O)R_(a),—OC(═O)OR_(a), —OC(═O)NR_(a)R_(b), —NR_(a)SO₂R_(b) or a radical of theformula —Y-Z-R_(a) where Y is alkanediyl, substituted alkanediyl or adirect bond, alkanediyl refers to a divalent alkyl with two hydrogenatoms taken from the same or different carbon atoms, Z is —O—, —S—,—S(═O)—, —S(═O)₂—, —N(R_(b))—, —C(═O)—, —C(═O)O—, —OC(═O)—,—N(R_(b))C(═O)—, —C(═O)N(R_(b))- or a direct bond, wherein R_(a), R_(b)and R_(c) are the same or different and independently hydrogen, amino,alkyl, substituted alkyl (including halogenated alkyl), aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocycle orsubstituted heterocycle or wherein R_(a) and R_(b) taken together withthe nitrogen atom to which they are attached form a heterocycle orsubstituted heterocycle.

The term “one pot reaction”, (also referred to herein as a “one potsynthesis”) refers to a multi-step chemical reaction carried out in areaction vessel. Typically, a reaction intermediate is generated in aninitial step of reaction, the intermediate is then reacted in situ withother component(s) present in or introduced to the same vessel. Thereaction intermediate generated is not isolated but serves directly as areactant in a next step of reaction. For example, in one embodiment ofthe instant invention, one or more free hydroxy groups of a taxane(e.g., paclitaxel) are protected, the protected taxane intermediate isnot isolated and is used directly in a next step of N-acylation wherebya t-butoxycarbonyl (t-Boc) group is attached to the nitrogen of theamide group at the C-3′ position.

II. Process for Protecting a Paclitaxel or a Related Taxane Thereof

As noted above, the present invention relates to a semi-synthesis ofpaclitaxel derivatives useful in the preparation of docetaxel. Inparticular, one embodiment of the present invention provides a processcomprising protecting one or more of the free hydroxy groups at any ofthe C-7, C-10 and C-2′ positions, and introducing a t-Boc group at thenitrogen of the amide group at the C-3′ position of a compound ofFormula (I) to provide a protected paclitaxel derivative having an urealinkage therein. One embodiment provides a process of protecting thehydroxy group(s) and introducing the t-Boc group, the processcomprising, in one reaction vessel, combining a compound of Formula (I)with a base, a hydroxy protecting agent and a t-Boc agent. The phrase“t-Boc agent” as used herein refers to a reagent that introduces a t-Bocgroup to the nitrogen of the amide group at the C-3′ position, in otherwords, the t-Boc agent further acylates the nitrogen of the amide group.Suitable “t-Boc agent” can be the same as those hydroxy protectingagents having a t-Boc moiety, for example, Boc₂O. The t-Boc agent isselected to react with the amide group in the presence of a base afterthe reactive hydroxy groups at the C-2′, C-7 and/or C-10 positions havebeen protected. Reaction Scheme 1 is shown below to illustrate thisprocess:

wherein,

-   -   R¹ is alkyl, alkenyl or aryl;    -   R², R³ and R⁴ are the same or different and independently a        hydroxy protecting group; and    -   X, Y and Z are the same or different and independently hydroxy        or protected hydroxy.

The protecting step provides protection to one or more reactive hydroxygroups in a compound of Formula (I). In one embodiment, when X and Z arefree hydroxy groups, as in paclitaxel (2) or cephalomannine (6), theprotection step comprises protecting the hydroxy groups at both the C-7and C-2′ positions. In another embodiment, X, Y and Z are all freehydroxy groups, as in 10-DAT (7), the protection step comprisesprotecting all three hydroxy groups at C-2′, C-7 and C-10 positions. Inyet another embodiment, X and Y are free hydroxy, and Z is already aprotected hydroxy, as in 10-deacetyl-7-xylosyl taxol (9), the protectionstep comprises protecting the free hydroxy groups at C-2′ and C-10positions.

In one embodiment, the same hydroxy protecting agent is used to protectall the available reactive hydroxy groups. In another embodiment,different hydroxy protecting agents can be used to protect the C-2′, C-7and/or C-10 positions. Typically, the free hydroxy group at the C-2′position is more reactive than the hydroxy group at the C-7, which is inturn more reactive than the hydroxy group at the C-10 positions. Thisleads to the preferential protection whereby the hydroxy group at C-2′will be protected first, followed by those at the C-7 and C-10positions. Thus, it is possible that the hydroxy protecting stepcomprises sequential steps of protecting the C-2′, C-7 and C-10positions, with a different protecting agent for each step. For example,C-2′ can be protected, using about one equivalent of a first hydroxyprotecting agent, followed by the protection of the C-7 position using asecond hydroxy protecting agent and, if necessary, followed by theprotection of the C-10 position using a third protecting agent. Thereaction can be carried out in the same reaction vessel withoutisolating any of the protected intermediates.

In a further embodiment, it is possible that the hydroxy protectingagent is the same as the t-Boc agent. For example, Boc₂O can be employedas a hydroxy protecting agent to protect, where appropriate, one or moreof the reactive hydroxy groups at any of the C-2′, C-7 and C-10positions. After the protection is completed, without isolating theprotected taxane intermediate, Boc₂O can be used to introduce a t-Bocgroup to the nitrogen of the amide group at the C-3′ position in thepresence of a base.

The foregoing steps of protecting hydroxy groups and introducing thet-Boc group are further described below in details.

General Method of Protection

The hydroxy groups at the C-2′, C-7 and/or C-10 positions of a taxane ofFormula (I) can be selectively protected using any of a variety ofhydroxy protecting agents, such as silylating, acylating, alkylatingagents and those agents forming acetal and ketal with the hydroxy group.The hydroxy protecting step can be carried out in the presence of a baseor an acid, depending on the hydroxy protecting agent(s) used.

One embodiment of the present invention provides the protection of oneor more hydroxy groups at the C-2′, C-7 and/or C-10 in the presence of abase. Formula (I) is:

wherein,

-   -   R¹ is alkyl, alkenyl or aryl; and    -   X, Y and Z are the same or different and independently hydroxy        or protected hydroxy.

In particular, the C-2′, C-7 and/or C-10 hydroxy group may be silylatedusing any of a variety of common silylating agents including, but notlimited to, tri(hydrocarbonyl)silyl halides and tri(hydrocarbonyl)silyltriflates. The hydrocarbonyl moieties of these compounds may beoptionally substituted and preferably are substituted or unsubstitutedalkyl or aryl. Representative silylating agents include, tribenzylsilylchloride, trimethylsilyl chloride, triethylsilyl chloride,dimethylisopropylsilyl chloride, dimethylphenylsilyl chloride and thelike.

Alternatively, selective acylation of the C-2′, C-7 and/or C-10 hydroxygroup can be achieved using any of a variety of common acylating agents,but not limited to substituted and unsubstituted carboxylic acidderivatives, e.g., carboxylic acid halides, anhydrides, dicarbonates,isocyanates and haloformates. Representative acylating agents include,di-tert-butyl dicarbonate (Boc₂O), dibenzyl dicarbonate, diallyldicarbonate, 2,2,2-trichloroethyl chloroformate, benzyl chloroformate,dichloroacetyl chloride, acetyl chloride or another common acylatingagent.

Alternatively, selective alkylation of the C-2′, C-7 and/or C-10 hydroxygroup can be achieved using any of a variety of common alkylatingagents, such as benzyl chloride and benzyl bromide.

According to the present invention, the protecting step is carried outin the presence of a base, such as, for example, DMAP, pyridine, TEA,LiOH, Li-t-OBu, n-BuLi, LiH, LiHMDS, KHMDS, K-t-OBu, NaH, NaHMDS,Na-t-OBu and mixtures of any two or more of the foregoing, such as amixture of n-BuLi/Li-t-OBu, and the hydroxy-protecting group is analkylating agent, silylating agent or acylating agent.

Exemplary reaction conditions are as follows: a taxane of Formula (I),or a mixture of taxanes, is dissolved in an organic solvent, such asanhydrous DCM (dichloromethane) or THF (tetrahydrofuran) or DMF(dimethyl formamide) or DMSO (dimethyl sulfoxide) or acetonitrile underan argon atmosphere at low to around room temperature. To this solutionis added DMAP (dimethylaminopyridine) or any of the lithium, sodium orpotassium base, such as Li-t-OBu, K-t-OBu, n-BuLi, a mixture ofn-BuLi/K-t-OBu or LiOH, followed by an hydroxy protecting agent, such asan acylating agent (e.g., di-tert-butyl dicarbonate), or an silylatingagent (e.g., triethyl silyl chloride) or any other hydroxy-protectingagents as described herein. The mixture is left at low to around roomtemperature until complete consumption of the starting material, asvisualized by TLC to afford a C-7, C-2′ and/or C-10 protected taxane ora mixture of C-7, C-2′ and/or C-10 protected taxanes. “Low temperature”as used herein refers to temperature between −78° C. to roomtemperature.

As noted above, the protecting step can be carried out using the samehydroxy protecting agent for all the available reactive hydroxy groupsat the C-2′, C-7 and/or C-10 positions, or using different hydroxyprotecting agent for each of the hydroxy groups to be protected. Inlight of the different reactivities of the hydroxy groups at the C-2,C-7 and C-10 positions as described above, one skilled in the art willreadily appreciate that by controlling the equivalency of a hydroxyprotecting agent in each step, C-2′, C-7 and/or C-10 can be protected bydifferent hydroxy protecting groups.

Another embodiment of the present invention provides the protection ofone or more hydroxy groups at the C-2′, C-7 and/or C-10 in the presenceof a catalytic amount of an acid. Formula (I) is:

wherein,

-   -   R¹ is alkyl, alkenyl or aryl; and    -   X, Y and Z are the same or different and independently hydroxy        or protected hydroxy.

In particular, the C-2′, C-7 and/or C-10 hydroxy group may be alkylatedwith an alkylating agent such as ethyl vinyl ether and methoxymethylchloride. Suitable acid includes p-toluenesulfonic acid and other proticacid. Protic acid refers to an acid that yields an H⁺ ion. Onlycatalytic amount of the acid is needed to initiate the protecting step.Typically, less than 1 equivalent of the acid is used, more typically,less than 0.5 equivalent of the acid is used, more typically, less than0.2 equivalent of the acid is used.

It is possible that one hydroxy group is protected in the presence of anacid, while the others are protected in the presence of a base. Forexample, C-2′ paclitaxel can be first protected using about oneequivalent of ethyl vinyl ether in the presence of a catalytic amount ofp-toluenesulfonic acid. Without isolating the C-2′ protected paclitaxel(i.e., 2′-OEE paclitaxel), a base and another hydroxy protecting agentare added. Advantageously, the amount of the base used is selected withthe expectation that some of it will be consumed by the acid that mightstill be present in the reaction mixture. In any event, one skilled inthe art will readily appreciate that all the reactive hydroxy groups ofa taxane of Formula (I) are to be protected by the same or differenthydroxy protecting groups.

Following protection of the hydroxy groups at the C-7, C-2′ and/or C-10positions of a taxane using the foregoing process, the introduction of at-Boc group at the nitrogen of the amide group of the taxane may beperformed in the same vessel without isolating the product of thehydroxy-protecting step according to the following method.

General Method of Introducing t-BOC at the Nitrogen of the Amide Group

The introduction of a tert-butoxycarbonyl (t-Boc) to the above protectedtaxane is also referred herein as a N-acylation step, whereby a t-Bocgroup replaces the hydrogen of the —NHC(O)R¹ group to provide a taxaneintermediate having an urea linkage at the C-3′ position, as representedby Formula (II) in Reaction Scheme 1. According to the presentinvention, the N-acylation step is carried out in a combined step byadding to the hydroxy-protected taxane in the same reaction vessel, abase and a t-Boc agent. Representative bases include DMAP, TEA, LiOH,n-BuLi, LiH, LiHMDS, KHMDS, NaH, NaHMDS or a mixture of any two or moreof the foregoing. In addition, the combined step may further comprisecombining the taxane with a metal alkoxide, wherein the metal isselected from the group consisting of Group I, II and III metals andtransition metals. Representative metal alkoxide includes, but is notlimited to Li-t-Bu, Na-t-Bu and K-t-Bu. Representative t-Boc agentincludes, but is not limited to, Boc₂O.

An exemplary reaction condition for introducing the t-Boc groupincludes, dissolving a C-7, C-2′ and/or C-10 protected taxane or amixture of C-7, C-2′ and/or C-10 protected taxanes in an organic solventunder an argon atmosphere at low to around room temperature. To thissolution is added a base, such as DMAP, TEA, LiOH, Li-t-OBu, n-BuLi,LiH, LiHMDS, KHMDS, K-t-OBu, NaH, NaHMDS, Na-t-Bu or a mixture of anytwo or more of the foregoing, followed by addition of a t-Boc agent. Themixture is left to react at low to room temperature until completeconsumption of the starting material, as visualized by TLC. A solutionof an acid, such as AcOH, in an organic solvent is added to the mixture,and the mixture is partitioned between saturated aqueous sodium hydrogencarbonate and mixtures of DCM and ethyl acetate. The combined organicextracts are dried and evaporated to give the crude protected taxanederivative, which can be further purified by column chromatography orcrystallized from a suitable solvent.

III. Taxane Starting Material

As noted above, the processes of the present invention may be utilizedto convert taxanes of Formula (I), and mixtures of taxanes, intoprotected taxane derivatives as represented by Formula (II), which canthen be used to further synthesize docetaxel. Representative taxanes ofFormula (I) include paclitaxel (2), cephalomannine (6), 10-deacetyltaxol (7), 7-xylosyl taxol (8) and 10-deacetyl-7-xylosyl taxol (9).However, other taxanes may also be present in the taxane startingmaterial without affecting the conversion of Formula (I) to Formula(III), as illustrated in Reaction Scheme 1. For example, in addition toone or more taxanes of Formula (I), other taxanes from a crude taxaneextract or in a waste taxane solution may also be present in thestarting material. These taxanes are a plurality of compounds of ageneric tetracyclic baccatin molecular framework as represented byFormula (IV):

wherein R_(A), R_(B), R_(C) and R_(D) represent substituents which varybetween the taxanes. More specifically, R_(A) is —OH, R_(B) is —OH or—OAc, R_(C) is ═O, and R_(D) is —OH or xylosyl. For example, when R_(A)is —OH, R_(B) is —OH, R_(C) is ═O and R_(D) is —OH, the foregoingstructure represents 10 deacetylbaccatin III (3), and when R_(A) is —OH,R_(B) is —OAc, R_(C) is ═O and R_(D) is —OH, the foregoing structurerepresents baccatin III (4), when R_(A) is —OAc, R_(B) is —OAc, R_(C) is—OH, and R_(D) is —OH, the forgoing structure represents 9-DHB (5).

It is desirable to adjust the amounts of the base and hydroxy protectingin order to fully protect all the reactive hydroxy groups in the taxanestarting material before the introduction of the t-Boc group to thenitrogen of the amide group. It can be readily appreciated by oneskilled in the art that, in doing so, the t-Boc agent for acylating theamide group is less likely to be consumed by any reactive free hydroxygroup.

In certain embodiments, the taxanes utilized in the processes of thepresent invention may be pure, purified or partially purified taxanes.Such purified and partially purified taxanes may be obtained by any of anumber of different methods well known in the art. For example,paclitaxel can be obtained by the methods described in U.S. Pat. No.6,136,989 to Foo et al. and references incorporated therein.

In other embodiments, the mixture of taxane utilized in the processes ofthe present invention may be a plurality of taxanes present in a crudetaxane extract or in a waste taxane solution or from synthesis. In thisway, the disclosed processes may be utilized for high yield and largescale conversion of taxanes present in a waste taxane solution intoprotected taxane derivatives, which can be used to further synthesizedocetaxel. Such waste taxane solutions may comprise (1) pooled wastestream fractions collected following the chromatographic separation andcollection of paclitaxel enriched fractions from a crude or partiallypurified taxane extract, and/or (2) pooled waste mother liquorscollected following the recrystallization of a crude or partiallypurified taxane extract of paclitaxel.

Representative waste taxane solutions may be obtained by a number ofdifferent methods, such as, for example, the methods disclosed in U.S.Pat. No. 6,136,989 to Foo et al., and other references cited therein,which patent is incorporated herein by reference in its entirety, andU.S. patent application Ser. No. 10/831,648, which application isassigned to the assignee of the present invention and is incorporatedherein by reference in its entirety. A representative method ofobtaining a waste taxane solution, which comprises pooled waste streamfractions, comprises the following extraction and column chromatographysteps.

Preparation of the Taxane-Containing Material

A suitable taxane-containing material is any tissue that contains a hightaxane content. Examples of suitable taxane-containing material includetissues from various species of Yew plants comprising the genus Taxus,most preferably the roots and needles of ornamental Yew plants such asT. canadensis, T. x media spp Hicksii, T. x dark green spreader andHill., T. chinensis, T. wallichiana, T. cuspidata, T. globosa, T.sumatrana, T. marei and T. floridana, and the bark of T. brevifolia orT. yunnanensis. Other suitable material include cultures of planttissues obtained from a Taxus species.

In a typical practice, such as set forth in U.S. Pat. No. 6,139,989, thetaxane-containing material is either pulverized, chipped or otherwiseground into small pieces so as to increase efficiency of a solventextraction. The taxane-containing material may also optionally be dried.Taxane-containing cell culture, cells, microorganisms and fermentationbroths will typically be concentrated prior to solvent extraction. Cellsand microorganisms can be processed as whole cells or cell paste orpulver.

Extraction

The taxane-containing material may be initially extracted by contactingthe material with an organic solvent, usually for a prolonged period ofat least 8 hours and typically for about 3 days with or without physicalagitation to promote formation of a crude organic extract containing aplurality of taxanes. The extraction may employ any of the solventsystems that are known to be used for the extraction of paclitaxel,including but not limited to, acetone, methanol, ethanol, ethyl acetate,methylene chloride, chloroform, mixtures thereof, and mixturescontaining an aqueous component of up to 60%. These solvents aretypically added in an amount of about 4-20 liter per kg of thetaxane-containing material to prepare the crude organic extract.Reference is made for example, to U.S. Pat. No. 6,136,989 and thepublications cited therein which provide a non-exclusive description ofseveral solvent systems that may be used to prepare an organic extractcontaining a plurality of taxanes.

In one embodiment, the organic solvent is a polar organic solvent,typically an alcohol. For some embodiments, methanol is preferredbecause of its low cost, ease of removal and efficiency of taxaneextraction. In one embodiment, about 6-15 liters of methanol is addedfor every kg of taxane-containing material to be extracted. Theextraction is accelerated by agitating the taxane-containing material,for example, by stirring or percolating the methanol with thetaxane-containing material for about 1-5 days at a temperature betweenroom temperature and about 60° C., most typically at about 40° C. Whenthe taxane-containing material contains a paclitaxel content of at least0.005%, methanol extraction for three days as described above recoversat least 90% of the available paclitaxel from the taxane-containingmaterial, in addition to a plurality of other taxanes, to form a crudemethanol extract containing about 0.1-0.5% paclitaxel and having anoverall solid content of about 0.5-5% (w/v).

The large volume of methanol extract thus obtained is optionallyconcentrated, typically about 10-30 fold by evaporation to obtain amethanol extract concentrate having a solid content of about 100-400g/L.

Liquid-Liquid Extraction

The crude organic extract may be subsequently enriched for taxanes byperforming 1-3 liquid-liquid extractions by mixing the organic extractwith a non-miscible, organic solvent to form a two phase system whereinone phase contains the plurality of taxanes. Generally, the two phasesystem includes a polar phase. Optionally, the taxane-containing phaseis selected and concentrated by evaporation to form a concentratedextract having a solid content of about 100-400 g/L and a paclitaxelpurity of about 1-4%. In some embodiments, water is included to helpremove preferentially water soluble materials and the less polar solventis selected to remove undesirable compounds such as waxes, lipids,pigments, and sterols that are found in different amounts depending onthe taxane-containing material used. Typical solvents for liquid-liquidpartitioning include hexane, and methylene chloride. Methylene chloridehas generally been found to be suitable for liquid-liquid extraction oftaxane-containing material especially when the solvent used for thecrude organic extract is an alcohol.

The concentrated extract obtained is optionally evaporated and theresidue is re-dissolved in a solvent for loading onto a silicachromatography matrix.

Other example methods of performing a liquid-liquid extraction areillustrated in U.S. Pat. Nos. 5,475,120, 5,380,916, and 5,670,673 to Raoand references cited therein, and also in U.S. Pat. Nos. 5,618,538 and5,480,639 to ElSohly et al. and references cited therein. These methodsor variants thereof may alternatively be used in lieu of the embodimentsdescribed. Furthermore, liquid-liquid extraction may be omittedaltogether when a plant extract containing high taxane levels isobtained by other methods such as for example, by interveningprecipitation, crystallization or chromatography steps. One example ofsuch a method is found in PCT Publication Nos. WO 98/07712 by Zamir etal, which uses a precipitation step immediately after obtaining aninitial organic extract to obtain a paclitaxel fraction that may beabout 1% or higher.

Silica Gel Column Chromatography

As further set forth in U.S. Pat. No. 6,136,989, the concentratedextract may be further purified by normal phase silica chromatography.As used herein, silica chromatography generally refers to the process ofcontacting a sample dissolved in a feed solvent with a silica matrixthen eluting the silica matrix with an eluting solvent to obtain afraction enriched with a desired component.

The dimensions of the first silica column are selected according to thequantity and purity of the solids to be separated. In one embodiment ofa pilot scale process, about 250 grams of solids are dissolved in about0.75 liters of feed solvent which is then chromatographed over a Silicacolumn of about 1.5-inches×10-feet. In another embodiment, about 40-50kg of solids are dissolved in about 100-200 liters of feed solvent, andchromatographed over a Silica column of about 18-inches×10-feet.

It has also been shown that a layer of about 1-15 cm of Celite,preferably about 2-8 cm, on top of the silica column is recommended as acolumn prefilter which substantially decreases the loading time of thesample. It has further been shown that the optimal eluting solvent forthe Silica column should be a hexane/acetone mixture at a ratio of about3:1 or a DCM/ethyl acetate mixture at a ratio of about 7:3. The ‘heartcut’ fractions containing at least 2% paclitaxel are pooled and furtherpurified, for example, according to the process set forth in U.S. Pat.No. 6,136,989. The remaining waste stream fractions, which contain aplurality of taxanes, including, paclitaxel, 10-deacetylbaccatin III(10-DAB), baccatin III (BACC III), 9-dihydro-13-acetylbaccatin III(9-DHB), cephalomannine, 10-deacetyl taxol (10-DAT), 7-xylosyl taxol and10-deacetyl-7-xylosyl taxol are pooled into a waste taxane solution forfurther processing according to the present invention.

Further Purification Steps

As set forth in more detail in U.S. Pat. No. 6,139,989, the paclitaxelenriched ‘heart cut’ fractions obtained from the foregoingchromatography step may be further purified through one or moreadditional chromatographic or recrystallization steps. Any waste streamfractions or waste mother liquors collected during such additionalpurification steps may also be pooled and added to the waste taxanesolution for further processing according to the present invention.

IV. Process of N-Deacylation of the Protected Taxane Intermediate Havingan Urea Linkage

According to the present invention, a protected taxane of Formula (II)having an urea linkage at the C-3′ position further undergoes aN-deacylation step to remove the —C(O)R¹ group in the presence of abase. As illustrated in Reaction Scheme 2, a protected docetaxel, asrepresented by Formula (III) is thus provided:

wherein,

-   -   R¹ is alkyl, alkenyl or aryl; and    -   R², R³ and R⁴ are the same or different and independently a        hydroxy protecting group.

In one embodiment, R¹ is phenyl. In another embodiment, R¹ is2-(2-butenyl). In particular, when R¹ is 2-(2-butenyl), compound ofFormula (II) is a protected cephalomannine, whose subsequent conversionto docetaxel has been described in U.S. application Ser. No. 10/790,622(hereafter referred as the '622 application). The '622 application isassigned to the assignee of the present invention and is incorporatedherein by reference in its entirety.

Suitable base includes metal hydroxide and metal alkoxide. Exemplarybase can be, but are not limited to, LiOH, NaOH, Ca(OCH₃)₂, or NaOCH₃.In one embodiment, the base is used in excess in order to avoidhydrolyzing any of the protected hydroxy group. For example, when thebase is LiOH, two or more equivalents of LiOH is used. Typically, 5 ormore equivalents of LiOH is used, and more typically, 10 or moreequivalents of LiOH is used. In a further embodiment, a peroxide can beused in conjunction with the base in the N-deacylation step.Representative peroxide includes, but is not limited to, H₂O₂, t-butylhydroperoxide (TBHB) and peroxy acid such as m-chloroperoxybenzoic acid(mCPBA). An exemplary N-deacylation condition includes the use of 20equivalents of 30% H₂O₂ with 10 equivalents of LiOH.

After the removal of the —C(O)R¹ group, a C-2′, C-7 and C-10 protecteddocetaxel is obtained, as represented by Formula (III). The protecteddocetaxel can then be subjected to hydrolysis conditions to afforddocetaxel.

V. Process for Preparing Docetaxel

As noted above, the C-7, C-2′ and/or C-10 hydroxy protected taxanederivatives prepared according to the foregoing semi-synthetic processesmay be utilized to further synthesize docetaxel. In this regards, in oneembodiment, the present invention provides an overall process forpreparing docetaxel from paclitaxel, paclitaxel derivative or paclitaxelcontaining material, the process comprising:

-   -   (1) protecting one or more hydroxy groups at the C-2′, C-7 and        C-10 positions of a compound of Formula (I):        wherein, R¹ is alkyl, alkenyl or aryl; and X, Y and Z are the        same or different and independently hydroxy or protected        hydroxy, to provide a hydroxy-protected taxane intermediate;    -   (2) introducing a t-Boc group at the nitrogen site of the amide        group to provide a protected taxane intermediate with an urea        linkage at the C-3′ position;    -   (3) selectively removing the —C(O)R¹ group of the protected        taxane intermediate with an urea linkage to provide a C-2′, C-7        and C-10 protected docetaxel; and    -   (4) converting C-2′, C-7 and C-10 hydroxy-protected docetaxel to        docetaxel,    -   wherein the step of protecting one or more hydroxy groups at        C-2′, C-7 and C10 positions and introducing a t-Boc group at the        nitrogen site of the amide group of the taxane comprises        combining, in a one pot reaction, the taxane of Formula (I) with        a base, a hydroxy-protecting group and a t-Boc agent; and        wherein the step of removing the —C(O)R¹ group of the urea        intermediate comprises subjecting the urea intermediate to a        base.

In another embodiment, the present invention provides an overall processfor preparing docetaxel from an initial mixture of taxanes, wherein theinitial mixture comprises paclitaxel, and at least one additional taxaneselected from 10 deacetylbaccatin III, baccatin III, cephalomannine,9-dihydro-13-acetylbaccatin III, 10-deacetyl taxol, 7-xylosyl taxol and10-deacetyl-7-xylosyl taxol, the process comprising:

-   -   protecting the hydroxy groups at the C-7 and C-2′ positions of        paclitaxel;    -   introducing a t-Boc group at the nitrogen of the amide group at        the C-3′ position of paclitaxel to provide a protected        paclitaxel derivative having an urea linkage at the C-3′        position;    -   selectively removing the benzoyl group from the urea linkage to        provide a protected docetaxel; and    -   converting the protected docetaxel to docetaxel by removing the        hydroxy-protecting groups at the C-7, C-2′ and C-10 positions,    -   wherein the step of protecting the hydroxy groups at C-2′ and        C-7 positions, and introducing a t-Boc group at the nitrogen        site of the amide group of paclitaxel are carried out in a one        pot reaction wherein the mixture containing paclitaxel is        combined with a first base, a hydroxy protecting agent and a        t-Boc agent; and wherein the step of selectively removing the        benzoyl group comprises subjecting the protected paclitaxel        derivative having the urea linkage to a second base.

In a further embodiment, the step of protecting the hydroxy groups ofpaclitaxel further comprises protecting one or more hydroxy groups ofeach taxanes in the mixture having free hydroxy groups at any of theC-2′, C-7 and C-10 positions.

The C-7, C-2′ and C-10 protected docetaxel derivatives may be convertedto docetaxel by a number of different deprotection methods, such as, forexample, the methods disclosed in U.S. patent application Ser. Nos.10/683,865 and 10/790,622, which applications are assigned to theassignee of the present invention and are incorporated herein byreference in their entireties, and U.S. Pat. Nos. 6,365,750 and6,307,071, and the references cited therein, which patents andreferences are incorporated herein by reference in their entireties.

VI. Preparation of Docetaxel from Primary Amine Derivatives ofPaclitaxel

As noted above, the present invention also provides a process forpreparing docetaxel via an intermediate of primary amine derivative ofpaclitaxel. The process can be illustrated in Reaction Scheme 3.

In particular, a paclitaxel or a derivative thereof as represented byFormula (I) is subjected to nitrosation condition whereby the amidegroup at the C-3′ position is converted to a N-nitrosoamideintermediate, as represented by Formula (V). Suitable nitrosationreagent includes, but is not limited to, NaNO₂, LiNO₂, KNO₂ and otherlike metal nitrites. Advantageously, an acid, such as acetic acid, ispresent in the nitrosation step. Alternatively, N₂O₄ gas can be used toprovide the N-nitrosoamide intermediate.

Under a suitable hydrolysis condition, which typically comprisessubjecting the N-nitrosoamide intermediate to a metal hydroxide, or amixture of metal hydroxide and a peroxide, a N-nitrosoamine intermediateis obtained, as represented by Formula (VI). Representative metalhydroxide includes, but not limited to LiOH and NaOH. Representativeperoxide includes, but is not limited to, H₂O₂, t-butyl hydroperoxide(TBHB) and peroxy acid such as m-chloroperoxybenzoic acid (mPCBA). Inone embodiment, LiOH is used. In another embodiment, a mixture of LiOHand H₂O₂ are used.

The nitrosoamine intermediate further undergoes reduction to afford aprimary amine derivative of paclitaxel, as represented by Formula (VII).Typical reduction condition includes, but is not limited to Raneynickel, palladium on carbon or platinum on carbon in the presence ofhydrogen gas.

Direct conversion of the primary amine derivative of paclitaxel todocetexel can be accomplished according the process as described in the'622 application.

Accordingly, the present invention further provides an alternativeoverall process of converting a paclitaxel or a derivative thereof todocetaxel comprising:

-   -   (1) introducing a nitroso group at the nitrogen of the amide        group at the C-3′ position of a compound of Formula (I):        wherein, R¹ is alkyl, alkenyl or aryl, and X, Y and Z are the        same or different and independently hydroxy or protected        hydroxy, to provide a N-nitrosoamide intermediate;    -   (2) hydrolyzing the N-nitrosoamide intermediate to provide a        N-nitrosoamine intermediate;    -   (3) reducing the N-nitrosoamine intermediate to provide a        primary amine intermediate; and    -   (4) converting the primary amine derivative to docetaxel.

Specifically, when R¹ is phenyl, the compound of Formula (I) can bepaclitaxel, when R¹ is 2-(2-butenyl), the compound of Formula (I) can becephalomannine.

In another embodiment, the present invention provides an overall processfor preparing docetaxel from an initial mixture of taxanes, wherein theinitial mixture comprises a compound of Formula (I), in particularly,paclitaxel, and at least one additional taxane selected from 10deacetylbaccatin III, baccatin III, cephalomannine,9-dihydro-13-acetylbaccatin III, 10-deacetyl taxol, 7-xylosyl taxol and10-deacetyl-7-xylosyl taxol, the process comprising:

-   -   introducing a nitroso group at the nitrogen of the amide group        at the C-3′ position of a compound of Formula (I):        wherein, R¹ is alkyl, alkenyl or aryl, and X, Y and Z are the        same or different and independently hydroxy or protected        hydroxy, to provide a N-nitrosoamide intermediate;    -   hydrolyzing the N-nitrosoamide intermediate to provide a        N-nitrosoamine intermediate;    -   reducing the N-nitrosoamine intermediate to provide a primary        amine intermediate; and    -   converting the primary amine derivative to docetaxel.

EXAMPLES

The following Examples disclose a representative process forsynthesizing a protected taxane derivative from paclitaxel or paclitaxelcontaining material, and the subsequent conversion of such derivativesto docetaxel. Unless otherwise noted, all scientific and technical termshave the meanings as understood by one of ordinary skill in the art.

Example 1 Protection of C-7, C-2′ and/or C-10 Hydroxy Groups in a OnePot Reaction

As shown in FIG. 1, to a stirred solution of paclitaxel or paclitaxelcontaining material, in an organic solvent, such as THF, at around lowto room temperature under an argon atmosphere was treated with ahydroxy-protecting agent, such as Boc₂O, dichloroacetyl chloride, acetylchloride, TESCI or like reagents in the presence of a base, such as4-(N,N-dimethylamino)pyridine or n-BuLi or a mixture of n-BuLi/Li-t-OBuor like bases. The reaction was stirred at this temperature for a periodbetween 30 minutes to 2 hours until complete consumption of the startingmaterials, as evidenced by TLC.

Alternatively, to a stirred solution of paclitaxel or paclitaxelcontaining material, in an organic solvent, such as THF, at around lowto room temperature under an argon atmosphere can be treated with ahydroxy-protecting agent such as ethyl vinyl ether, in the presence of acatalytic amount of p-toluenesulfonic acid.

The reaction mixture after the protecting step is used directly in thenext step of N-acylation without isolating any of the reactionintermediate.

Preparation of N-Acyl Paclitaxel Derivative

To a solution of the C-7, C-2′ and/or C-10 protected paclitaxelderivative in an organic solvent, such as the freshly distilled THF,under argon atmosphere at low to around room temperature most preferablyat 20° C., was added drop wise a solution of a base, such as DMAP orn-BuLi in hexanes or like bases. After stirring for 30 min to 1 hr atthis temperature, a solution of Boc₂O in anhydrous THF was added dropwise to the mixture. The solution was kept at that temperature for anadditional 1 to 3 hrs, or until complete consumption of the startingmaterial, as evidenced by TLC, before addition of a solution of an acidin an organic solvent, such as 5% AcOH in THF. The mixture was thenpartitioned between saturated aqueous sodium hydrogen carbonate andmixtures of dichloromethane and ethyl acetate. Evaporation of theorganic layer yielded a crude paclitaxel derivative having an urealinkage, i.e., a paclitaxel N-t-Boc derivative, which could be furtherpurified by either column chromatography or crystallization to yield apure protected paclitaxel derivative or used directly for the next stepin the synthesis.

Alternatively, DMAP (0.1 mmol) was added to a stirred solution of thepaclitaxel (1.0 mmol) in dry acetonitrile followed by BOC₂O (1.1 mmol).After stirring for 4 h at room temperature, all starting material wasconsumed (TLC). The reaction mixture was evaporated at room temperatureand the residue partitioned between ether and aqueous KHSO₄. The organicextract was thoroughly washed in turn with aqueous solution of KHSO₄ andNaHCO₃ and finally brine and dried over MgSO₄. Evaporation to completedryness left a light yellow residue that was purified by columnchromatography to afford the paclitaxel N-t-Boc derivative.

N-Debenzoylation of the Paclitaxel N-t-Boc Derivative

To the above solution in tetrahydrofuran was added a 1.0 N solution oflithium hydroxide. The solution was stirred for 12 h at roomtemperature. After removal of tetrahydrofuran in vacuo, the basicaqueous residue was acidified by the addition of 10% acetic acid andextracted with ether. Drying (MgSO₄) and concentration afforded thecrude material that was purified by column chromatography to afford thepure white C-2′, C-7 and C-10 protected docetaxel. (Note: The followingcould also be used: 10 equiv. LiOH, 20 equiv. 30% H₂O₂, 3:1 THF:H₂O, 0°C.).

Example 2 Synthesis of Docetaxel

As further shown in FIG. 1, C-2′, C-7 and C-10 protected docetaxel washydrolyzed using formic acid to remove the C-7 and/or C-10 t-Bocprotecting group and then with a mixture of NaHCO₃/Na₂CO₃/H₂O₂ todeprotect the C-2′ and/or C-10 acetate groups to yield docetaxel. In theevent that the C-2′ protecting group is ethoxyethyl, the deprotection iscarried out under acidic condition, such as in the presence of aceticacid. Detailed description of deprotection at the C-2′, C-7 and C-10positions are described in U.S. Patent application Ser. No. 10/790,622,which application is assigned to the assignee of the present inventionand is incorporated herein by reference in its entirety.

Example 3 Synthesis of the Primary Amine Derivative of Paclitaxel

Nitrosation

To a solution of paclitaxel (0.76 mmol) or a paclitaxel containingmaterial in glacial acetic acid (2.5 ml) and acetic anhydride (5 ml) at0° C. is added NaNO₂ (7.6 mmol). The resulting solution can be stirredunder argon at 0° C. for 16 h and then poured over ice and extractedwith diethyl ether. The combined organic extracts can be washed withwater, 5% Na₂CO₃, water and saturated NaCl and dried over MgSO₄. The dryextracts can be filtered and then concentrated in vacuo, and the crudeproduct is purified by column chromatography using mixtures ofhexane-ethyl acetate to afford the pure product.

Hydrolysis

To the above solution in tetrahydrofuran is added a 1.0 N solution oflithium hydroxide. The solution was stirred for 12 h at roomtemperature. After the removal of tetrahydrofuran in vacuo, the basicaqueous residue can be acidified by the addition of 10% acetic acid andextracted with ether. Drying (MgSO₄) and concentration afforded thecrude material which can be purified by column chromatography to affordthe pure primary amine taxane intermediate. (Note: The following canalso be used: 10 equiv. LiOH, 20 equiv. 30% H₂O₂, in 3:1 THF:H₂O)

Reduction

The above hydrolyzed product can then be dissolved in ethanol at roomtemperature and Raney-Nickel is added in one portion to the stirredsolution. The reaction mixture is stirred at this temperature andtreated with hydrogen, until the complete consumption of the startingmaterial. The reaction mixture can be filtered and the filtrateevaporated. The residue is then dissolved in an inert solvent such asdichloromethane and worked up as usual. The crude product can bepurified by column chromatography using mixtures of dichloromethane andethyl acetate to afford the pure primary amine derivative of paclitaxel.

Conversion to Docetaxel

The primary amine derivative of paclitaxel (0.091 mmol) can be dissolvedin ethyl acetate (9.1 ml) and a saturated solution of NaHCO₃ (9.1 ml)was added. To this biphasic mixture Boc₂O (0.18 mmol) can be added. Themixture is stirred for 12 h at room temperature and TLC showed completeconsumption of the starting material. The reaction can be worked up asusual and the residue purified by column chromatography using mixturesof dichloromethane and ethyl acetate or acetone to give docetaxel.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

From the foregoing, it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A process for converting paclitaxel or paclitaxel containing materialto docetaxel by protecting a compound of Formula (I):

wherein, R¹ is alkyl, alkenyl or aryl; and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy, the processcomprising: protecting one or more hydroxy groups at the C-2′, C-7 andC-10 positions of the taxane; and introducing a t-Boc group at thenitrogen of the amide group at the C-3′ position of the taxane toprovide a C-2′, C-7, C-10 and N-t-Boc protected paclitaxel derivative,wherein the steps of protecting one or more hydroxy groups andintroducing the t-Boc group comprises combining, in a one pot reaction,the taxane with a hydroxy protecting group and a t-Boc agent.
 2. Theprocess of claim 1 wherein the hydroxy protecting groups at the C-2′,C-7 and C-10 positions are the same.
 3. The process of claim 1 whereinthe hydroxy protecting groups at the C-2′, C-7 and C-10 positions aredifferent.
 4. The process of claim 1 wherein the step of protecting oneor more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxaneis carried out in the presence of a base.
 5. The process of claim 4wherein the base is DMAP, pyridine, TEA, LiOH, n-BuLi, LiH, LiHMDS,KHMDS, NaH, NaHMDS, or a mixture thereof
 6. The process of claim 5wherein the base further comprises a metal alkoxide, wherein the metalis a Group I, II, III or transition metal.
 7. The process of claim 6wherein the metal alkoxide is Li-t-OBu, Na-t-OBu or K-t-OBu.
 8. Theprocess of claim 4 wherein the step of protecting one or more hydroxygroups at the C-2′, C-7 and C-10 positions of the taxane comprisescombining the taxane with a base and a hydroxy-protecting group in anorganic solvent, and wherein the base is DMAP, pyridine, TEA, LiOH,Li-t-OBu, n-BuLi, K-t-OBu or a mixture thereof, and thehydroxy-protecting group is an alkylating agent, silylating agent oracylating agent.
 9. The process of claim 8 wherein thehydroxy-protecting group is tert-butoxycarbonyl (t-Boc),benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc),9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl,trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl,diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl,acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl ortrifluoroacetyl.
 10. The process of claim 9 wherein the base is DMAP orn-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl ordichloroacetyl.
 11. The process of claim 1 wherein the step ofprotecting one or more hydroxy groups at the C-2′, C-7 and C-10positions of the taxane is carried out in the presence of an acid. 12.The process of claim 11 wherein the acid is p-toluenesulfonic acid andthe hydroxy protecting group is ethoxyethyl or methoxymethyl.
 13. Theprocess of claim 1 wherein the t-Boc agent is Boc₂O.
 14. The process ofclaim 1 wherein the taxane is paclitaxel or paclitaxel containingmaterial.
 15. A process for preparing docetaxel from a taxane of Formula(I):

wherein, R¹ is alkyl, alkenyl or aryl; and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy, the processcomprising: protecting one or more hydroxy groups at the C-2′, C-7 andC-10 positions of the taxane; introducing a t-Boc group at the nitrogenof the amide group at the C-3′ position of the taxane to provide aprotected paclitaxel derivative having an urea linkage at the C-3′position; selectively removing the —C(O)R¹ group from the urea linkageto provide a protected docetaxel; and converting the protected docetaxelto docetaxel by removing the hydroxy-protecting groups at the C-2′, C-7and C-10 positions, wherein the step of protecting one or more hydroxygroups at C-2′, C-7 and C-10 positions, and introducing the t-Boc groupat the nitrogen site of the amide group of the taxane comprisescombining, in a one pot reaction, the taxane of Formula (I) with ahydroxy protecting agent and a t-Boc agent, and wherein the step ofselectively removing the —C(O)R¹ group comprises subjecting theprotected paclitaxel derivative having the urea linkage to a first base.16. The process of claim 15 wherein the hydroxy protecting groups at theC-2′, C-7 and C-10 positions are the same.
 17. The process of claim 15wherein the hydroxy protecting groups at the C-2′, C-7 and C-10positions are different.
 18. The process of claim 15 wherein the step ofprotecting one or more hydroxy groups at the C-2′, C-7 and C-10positions of the taxane is carried out in the presence of a second base.19. The process of claim 18 wherein the second base is DMAP, pyridine,TEA, LiOH, n-BuLi, LiH, LiHMDS, KHMDS, NaH, NaHMDS, or a mixturethereof.
 20. The process of claim 19 wherein the second base furthercomprises a metal alkoxide, wherein the metal is a Group I, II, III ortransition metal.
 21. The process of claim 20 wherein the metal alkoxideis Li-t-OBu, Na-t-OBu or K-t-OBu.
 22. The process of claim 18 whereinthe step of protecting one or more hydroxy groups at the C-2′, C-7 andC-10 positions of the taxane comprises combining the taxane with a baseand a hydroxy-protecting group in an organic solvent, and wherein thebase is DMAP, pyridine, TEA, LiOH, Li-t-OBu, n-BuLi, K-t-OBu or amixture thereof, and the hydroxy-protecting group is an alkylatingagent, silylating agent or acylating agent.
 23. The process of claim 22wherein the hydroxy-protecting group is tert-butoxycarbonyl (t-Boc),benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc),9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl,trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl,diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl,acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl ortrifluoroacetyl.
 24. The process of claim 23 wherein the base is DMAP orn-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl ordichloroacetyl.
 25. The process of claim 15 wherein the step ofprotecting one or more hydroxy groups at the C-2′, C-7 and C-10positions of the taxane is carried out in the presence of an acid. 26.The process of claim 25 wherein the acid is p-toluenesulfonic acid andthe hydroxy protecting group is ethoxyethyl or methoxymethyl.
 27. Theprocess of claim 15 wherein the t-Boc agent is Boc₂O.
 28. The process ofclaim 15 wherein the taxane is paclitaxel or paclitaxel containingmaterial.
 29. The process of claim 15 wherein the first base is a metalhydroxide or a metal alkoxide.
 30. The process of claim 29 wherein themetal hydroxide is LiOH, NaOH or KOH.
 31. The process of claim 29wherein the metal alkoxide is calcium methoxide, sodium methoxide,lithium methoxide or potassium methoxide.
 32. The process of claim 29wherein the first base is used in conjunction with a peroxide.
 33. Theprocess of claim 32 wherein the peroxide is H₂O₂, t-butyl hydroperoxide(TBHB) or m-chloroperoxybenzoic acid (mCPBA).
 34. The process of claim33 wherein LiOH is used in conjunction with H₂O₂.
 35. A process forpreparing docetaxel from an initial mixture of taxanes, wherein theinitial mixture comprises paclitaxel and at least one additional taxaneselected from the group of 10-deacetylbaccatin III,9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine,10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol, theprocess comprising the steps of: protecting the hydroxy groups at theC-2′ and C-7 positions of paclitaxel; introducing a t-Boc group at thenitrogen of the amide group at the C-3′ position of paclitaxel toprovide a protected paclitaxel derivative having an urea linkage at theC-3′ position; selectively removing the benzoyl group from the urealinkage to provide a protected docetaxel; and converting the protecteddocetaxel to docetaxel by removing the hydroxy-protecting groups at theC-7, C-2′ and C-10 positions, wherein the step of protecting the hydroxygroups at C-2′ and C-7 positions, and introducing a t-Boc group at thenitrogen site of the amide group of paclitaxel are carried out in a onepot reaction wherein the mixture containing paclitaxel is combined witha hydroxy protecting agent and a t-Boc agent; and wherein the step ofselectively removing the benzoyl group comprises subjecting theprotected paclitaxel derivative having the urea linkage to a first base.36. The process of claim 35 wherein the hydroxy protecting groups at theC-2′ and C-7 positions are the same.
 37. The process of claim 35 whereinthe hydroxy protecting groups at the C-2′ and C-7 positions aredifferent.
 38. The process of claim 35 wherein the step of protectingone or more hydroxy groups at the C-2′ and C-7 positions of paclitaxelis carried out in the presence of a second base.
 39. The process ofclaim 38 wherein the second base is DMAP, pyridine, TEA, LiOH, n-BuLi,LiH, LiHMDS, KHMDS, NaH, NaHMDS, or a mixture thereof.
 40. The processof claim 39 wherein the second base further comprises a metal alkoxide,wherein the metal is a Group I, II, III or transition metal.
 41. Theprocess of claim 40 wherein the metal alkoxide is Li-t-OBu, Na-t-OBu orK-t-OBu.
 42. The process of claim 38 wherein the step of protecting oneor more hydroxy groups at the C-2′ and C-7 positions of the taxanecomprises combining the taxane with the second base and ahydroxy-protecting group in an organic solvent, and wherein the secondbase is DMAP, pyridine, TEA, LiOH, Li-t-OBu, n-BuLi, K-t-OBu or amixture thereof, and the hydroxy-protecting group is an alkylatingagent, silylating agent or acylating agent.
 43. The process of claim 42wherein the hydroxy-protecting group is tert-butoxycarbonyl (t-Boc),benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc),9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl,trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl,diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl,acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl ortrifluoroacetyl.
 44. The process of claim 43 wherein the base is DMAP orn-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl ordichloroacetyl.
 45. The process of claim 35 wherein the step ofprotecting one or more hydroxy groups at the C-2′ and C-7 positions ofthe taxane is carried out in the presence of an acid.
 46. The process ofclaim 45 wherein the acid is p-toluenesulfonic acid and the hydroxyprotecting group is ethoxyethyl or methoxymethyl.
 47. The process ofclaim 35 wherein the t-Boc agent is Boc₂O.
 48. The process of claim 35wherein the first base is a metal hydroxide or a metal alkoxide.
 49. Theprocess of claim 48 wherein the metal hydroxide is LiOH, NaOH or KOH.50. The process of claim 48 wherein the metal alkoxide is calciummethoxide, sodium methoxide, lithium methoxide or potassium methoxide.51. The process of claim 48 wherein the first base is used inconjunction with a peroxide.
 52. The process of claim 51 wherein theperoxide is H₂O₂, t-butyl hydroperoxide (TBHB) or m-chloroperoxybenzoicacid (mCPBA).
 53. The process of claim 52 wherein LiOH is used inconjunction with H₂O₂.
 54. The process of claim 35 wherein the step ofprotecting the hydroxy group at the C-2′ and C-7 position of paclitaxelfurther comprises protecting one or more hydroxy groups at the C-2′, C-7and C-10 positions of each taxane in the initial mixture having ahydroxy group at these positions.
 55. The process of claim 35 whereinthe initial mixture comprises paclitaxel and at least two additionaltaxanes selected from 10-deacetylbaccatin III,9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine,10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol. 56.The process of claim 35 wherein the initial mixture comprises paclitaxeland at least three additional taxanes selected from 10-deacetylbaccatinIII, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine,10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol. 57.The process of claim 35 wherein the initial mixture comprisespaclitaxel, 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III,baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and10-deacetyl-7-xylosyl taxol.
 58. The process of claim 35 wherein theinitial mixture of taxanes is a waste taxane solution comprising one ormore of the following: pooled waste stream fractions collected during achromatographic separation of a crude or partially purified taxaneextract; and pooled waste mother liquors collected during arecrystallization of a crude or partially purified taxane extract. 59.The process of claim 58 wherein the waste taxane solution comprisespooled waste stream fractions collected during a chromatographicseparation of a crude taxane extract.
 60. The process of claim 58wherein the waste taxane solution comprises pooled waste streamfractions collected during chromatographic separations of both crude andpartially purified taxane extracts and pooled waste mother liquorscollected during recrystallizations of both crude and partially purifiedtaxane extracts.
 61. The process of claim 60 wherein the crude andpartially purified taxane extracts are obtained from taxane-containingmaterials from the genus Taxus or from synthesis.
 62. A process ofconverting a taxane of Formula (I)

wherein, R¹ is alkyl, alkenyl or aryl, and X, Y and Z are the same ordifferent and independently hydroxy or protected hydroxy, to docetaxel,the process comprising: introducing a nitroso group (—NO) at thenitrogen of the amide group at the C-3′ position of the taxane toprovide a N-nitrosoamide intermediate; hydrolyzing the N-nitrosoamideintermediate to provide a N-nitrosoamine intermediate; reducing theN-nitrosoamine intermediate to provide a primary amine intermediate; andconverting the primary amine derivative to docetaxel.
 63. The process ofclaim 62 wherein the step of introducing the nitroso group comprisescombining the taxane of Formula (I) with a nitrosation agent.
 64. Theprocess of claim 63 wherein the nitrosation agent is NaNO₂, LiNO₂, orKNO₂ in the presence of an acid.
 65. The process of claim 63 wherein thenitrosation agent is N₂O₄.
 66. The process of claim 62 wherein the stepof hydrolyzing the N-nitrosoamide intermediate comprises combining theN-nitrosoamide intermediate with a metal hydroxide and a peroxide. 67.The process of claim 66 wherein the metal hydroxide is LiOH and theperoxide is H₂O₂.
 68. The process of claim 62 wherein the step ofreducing the N-nitrosoamine intermediate comprises combining theN-nitrosoamine intermediate with a reducing agent selected from RaneyNickel, palladium on carbon in the presence of hydrogen gas and platinumon carbon in the presence of hydrogen gas.
 69. The process of claim 62wherein the compound of Formula (I) is paclitaxel or paclitaxelcontaining material.
 70. The process of claim 62 wherein the compound ofFormula (I) is part of a mixture comprising the compound of Formula (I),and one or more compounds selected from the group consisting ofpaclitaxel, 9-dihydro-13-acetylbaccatin III, cephalomannine, 10-deacetyltaxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol.
 71. The processof claim 70 wherein the initial mixture of taxanes is a waste taxanesolution comprising one or more of the following: pooled waste streamfractions collected during a chromatographic separation of a crude orpartially purified taxane extract; and pooled waste mother liquorscollected during a recrystallization of a crude or partially purifiedtaxane extract.
 72. The process of claim 71 wherein the waste taxanesolution comprises pooled waste stream fractions collected during achromatographic separation of a crude taxane extract.
 73. The process ofclaim 71 wherein the waste taxane solution comprises pooled waste streamfractions collected during chromatographic separations of both crude andpartially purified taxane extracts and pooled waste mother liquorscollected during recrystallizations of both crude and partially purifiedtaxane extracts.
 74. The process of claim 73 wherein the crude andpartially purified taxane extracts are obtained from taxane-containingmaterials from the genus Taxus or from synthesis.